The present invention relates to novel 1-alkylsulfonyl-2, 2-difluoro-3-carbamoyl-5-protected ribose derivatives and to a process using such compounds to prepare intermediate nucleobases to antiviral alpha and beta nucleosides. In particular the present invention relates to novel nucleobases which are intermediates to 2'-deoxy-2',2'-difluoro-beta-cytidine, an antiviral agent and anticancer agent.
The prior art synthesis of 2'-deoxy-2',2'-difluoro-beta-cytidine involves reaction of silylated cytosine with a dibenzylated ribose mesylate intermediate according to the following reaction (Equation 1): ##STR1##
Under conditions where substitution of the mesylate by cytosine is preceded by elimination of mesylate to give a charged intermediate (SN1), a mixture of alpha and beta anomers (the beta anomer is desired) is obtained. The alpha and beta nucleosides are deprotected in a conventional manner and then separated.
In classical methods of nucleoside synthesis, where there is an acylated hydroxy group on the neighboring 2-carbon of the ribose, the participation of the acyl group in the substitution reaction favors formation of the beta isomer (Goodman, L., Basic Principles in Nucleic Acid Chemistry, Volume 1, pp. 94-208, Academic Press, New York (1974)) as shown by the following reaction (Equation 2): ##STR2##
Since the dibenzylated ribose mesylate intermediate in 2'-deoxy-2', 2'-difluoro-beta-cytidine synthesis of 2'-deoxy-2', 2'-difluoro-beta-cytidine contains no 2-hydroxy group, such participation cannot occur.
In principle, substituents on either the 3- or 5-hydroxyls of ribose could be used to direct facial selectivity in such reactions. The 2-(methylsulfinyl)ethyl group has recently been recommended as a 3-OH protecting group which imparts good .beta.-selectivity in glycosylation reactions with 2-deoxyribose derivatives. Unfortunately, convenient methods for the introduction of this group are not currently available. See: Okauchi, T.; Kubota, H.; Narasaka, K., Chem. Lett. 801-804 (1989), and Ichikawa, Y.; Kubota, H.; Fujita, K.; Okauchi, T.; Narasaka, K., Bull. Chem. Soc. Japan, 62, 845-852 (1989); Wierenga, W.; Skulnick, H. I., Carbohydr. Res., 90, 41-52 (1981). In practice, relatively low levels of stereocontrol have generally been achieved by this strategy and the factors responsible are not always clear. Although bicyclic cations of type A and B below have been proposed as intermediates in such glycosylation reactions (Wierenga, W., et al., Carbohydr. Res., 90, 41-52 (1981)) their significance in influencing product ratios is a debatable point. ##STR3##
In situations where both the 3- and 5-hydroxyls are acylated, competition of both types of bicyclic cation for the nucleophile could result in a low level of stereoselection since they lead to products of opposite configuration.
The concept of using the substituent on the 3 hydroxy of deoxyribofuranose derivatives to direct beta synthesis is described by Ichikawa et al (Ichikawa, Y., et al., Bull. Chem. Soc. Japan, 62(3), 845-852 (1989)). They used a methylthioethyl substituent or especially its corresponding sulfoxide at the 3 position of a 2-deoxyribose sugar to successfully enhance beta substitution of silylated nucleophiles to form C-glycosides. Similarly, they formed predominantly beta S-glycosides when reacting the 2-deoxyribose sugar containing a 2-pyridylmethyl N-oxide protective group at the 3 position with trimethylsilyl sulfides. There was no disclosure of the use of nucleobases
Although both aryl and alkyl carbamates have been used for selective protection of sugar hydroxyls (Plusquellec, D., et al., Tetrahedron Let., 28, 4165-4168 (1987)) or to obtain crystalline sugar derivatives (Wolfrom, M. L., et al., J. Am. Chem. Soc., 62, 1151-1153 (1940)), no use is reported in the literature for the purpose of directing nucleobase addition to the beta anomeric carbon (C1) position in forming a nucleoside.
It is therefore an object of the present invention to provide novel intermediates which produce a high percentage yield of the beta anomer nucleoside, compared to the alpha anomer when used in the preparation of intermediates to 2'-deoxy-2',2'-difluoro-beta-cytidine and analogous compounds. Further, it is an object of the present invention to provide novel beta anomer nucleosides from the intermediate compounds. Further still, it is an object to provide a process for producing the compounds which is relatively economical and which particularly can be used in producing 2'-deoxy-2',2'-difluoro-beta-cytidine and other beta anomer nucleosides in bulk. These and other objects will become increasingly apparent by reference to the following description.